The overall objective of this multidisciplinary research program is to identify the mechanisms of accelerated graft arteriosclerosis (AGA) in heart transplant recipients in order to better identify and treat this disorder. The working hypothesis is that various causes of vascular injury during and after transplantation trigger multiple host and donor dependent responses resulting in AGA. Five projects and three core support units will address the objectives and hypotheses of this program. Project 1 will examine how the response of vascular endothelial cells to injury leads to AGA. The focus of this project will be to examine the role of the heterotrimeric G-protein signaling pathway and of cytotoxic lymphocyte- mediated apoptosis triggered by fas overexpression on endothelial cells. Project 2 will examine how cytomegalovirus (CMV) contributes to AGA. In particular, the role of non-permissive CMV infection and the interaction of CMV gene products with the p53 tumor suppressor gene product, platelet- derived growth factor (PDGF), and transforming growth factor beta (TGF beta) will be examined. Project 3 will examine the role of molecular mediators in the inflammatory and proliferative responses characteristic of AGA. The focus of this project will be on the growth-stimulating compounds TGF-beta and PDGF, and the anti-proliferative and vasodilating compound nitric oxide. Project 4 will examine the role of complement (C) and antibody in AGA, focusing on responses to ischemic, alloimmune, autoimmune and viral (CMV) injury. In particular, early and late C components will be examined separately, as will antibody responses to specific major histocompatibility complex (MHC) and heat shock protein (HSP) epitopes. Project 5 will examine the role of cell-mediated immunity to autologous (HSP, host-MHC), to allogeneic (donor MHC), and to exogenous (CMV) antigens in the development of AGA. In particular, the repertoire, function, and specificity of cyclosporine A-induced autoreactive T-cells in mediating AGA will be examined. The Administrative Core (Core A) will provide administrative and statistical support. The Pathology/Clinical Core (Core B) will process and bank human and animal tissues for study, and provide a central resource for quantifying pathologic changes. The animal core (Core C) will provide uniform animal heart transplants for in vivo studies. Each pathway examined in this Program will be studied using banked human tissues, dissected out with in vitro and in vivo animal models, and defined at the molecular and cellular levels. The molecular and cellular mechanisms identified in turn will form the basis for developing novel diagnostic and therapeutic strategies which can be translated back to patients.